1. Field
The present invention relates to granules, for oral administration in fluid form, of biologically active substances of the formula: ##STR1## in which X=carbon or nitrogen, Y=nitrogen or, if X is carbon, can also represent carbon,
R.sub.1 =H, OH, O-alkyl (1-4 C atoms), alkyl (1-4 C atoms) or a halogen, PA0 R.sub.2 =H, OH, O-alkyl (1-4 C atoms), alkyl (1-4 C atoms) or a halogen, PA0 R.sub.3 =H or alkyl (1-4 C atoms) PA0 1) 1-5 parts by weight of a sparingly soluble form of a compound of formula I; PA0 2) 0.3-3 parts by weight of a cellulose derivative which is soluble in water and in organic solvents; PA0 3) 4-20 parts by weight of a pharmaceutically acceptable polymer which is insoluble in water; and PA0 4) 40-250 parts by weight of a filler customary in pharmacy.
and the broken line indicates an extra bond which may or may not be present when Y is a carbon atom.
2. State of the art
Compounds of formula I are describe, inter alia, in U.S. Pat. Nos. 4,002,632 and 3,534,031. The form in which these compounds are used is generally the hydrochloride or other salt which is readily soluble in water.
In the case of orally administrable forms, these salts, which are readily soluble in water, have the problem that they have a very unpleasant taste and, moreover, have a local anaesthetic effect which is found to be particularly annoying.
In tablets, the unpleasant taste can be masked by adding auxiliaries; in the case of other oral administration forms this is found to be a problem which is difficult to solve.
The field of application of the compounds of formula I comprises, inter alia, a group of patients (e.g. elderly and disabled) for whom the tablet form is less suitable. For this group of patients an orally administrable fluid form would be very useful.
Because of the disadvantages outlined above, the readily soluble salts of the compounds of formula I cannot be used directly in a fluid administration form. In order to solve the problem, a suspension of an insoluble form of the active substance would have to be prepared.
In this context, the direct use of an insoluble form of the active substance, or the encapsulation of a readily soluble compound of formula I in a hydrophobic polymer, could be considered. However, the problem is then encountered that such substances are very difficult to suspend.
U.S. Pat. No. 4,447,437 discloses oral agents such as "granules". Oral agents according to that patent contain an active substance of formula I and pharmaceutically acceptable carriers or excipients. Examples of solid carriers and excipients include crystalline cellulose, cellulose derivatives, calcium carbohydroxycellulose, corn starch, potato starch, and mannitol.
European patent application 0,320,097 discloses the polymer Eudragit RS for use in a pharmaceutical preparation.
European patent application 0,319,061 to Akzo NV discloses an active substance of formula I in combination with Whitepsol 558, in a weight ratio of 1:100.
Problems which come to the fore with these preparations are: aggregation of the particles, settling of particles, and poor miscibility of the particles with water, as a result of which, when the particles are brought into suspension, some of the suspension will stick to the wall of the glass or plastic beaker and some will remain floating on the water surface. The dosage consequently becomes inaccurate.
The above problems can be reduced by adding surface-active substances. However, in view of possible side effects this is undesirable.